Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body:
1. Increased rate of protein synthesis in all cells of the body; PA1 2. Decreased rate of carbohydrate utilization in cells of the body; PA1 3. Increased mobilization of free fatty acids and use of fatty acids for energy. PA1 R.sub.2 is selected from: hydrogen, C.sub.1 -C.sub.6 alkyl, and C.sub.3 -C.sub.7 cycloalkyl, and where two C.sub.1 -C.sub.6 alkyl groups are present on one atom, they may be optionally joined to form a C.sub.3 -C.sub.8 cyclic ring, optionally including oxygen, sulfur or NR.sub.3a, where R.sub.3a is hydrogen, or C.sub.1 -C.sub.6 alkyl, optionally substituted by hydroxyl; PA1 X is selected from: hydrogen, --C.tbd.N, --(CH.sub.2).sub.q N(R.sub.2)C(O)R.sub.2, --(CH.sub.2).sub.q N(R.sub.2)C(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)SO.sub.2 (CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)SO.sub.2 R.sub.2, --(CH.sub.2) .sub.q N(R.sub.2)C(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)C(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q C(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q C(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q C(O)OR.sub.2, --(CH.sub.2).sub.q C(O)O(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q OR.sub.2, --(CH.sub.2).sub.q OC(O)R.sub.2, --(CH.sub.2).sub.q OC(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q OC(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q OC(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q C(O)R.sub.2, --(CH.sub.2).sub.q C(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)C(O)OR.sub.2, --(CH.sub.2).sub.q N(R.sub.2)SO.sub.2 N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q S(O).sub.m R.sub.2, and --(CH.sub.2).sub.q S(O).sub.m (CH.sub.2).sub.t aryl, where an R.sub.2, (CH.sub.2).sub.q and (CH.sub.2).sub.t group may be optionally substituted by 1 to 2 C.sub.1 -C.sub.4 alkyl, hydroxyl, C.sub.1 -C.sub.4 lower alkoxy, carboxyl, CONH.sub.2, S(O).sub.m CH.sub.3, carboxylate C.sub.1 -C.sub.4 alkyl esters, or 1H-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or 1H-tetrazol-5-yl groups which may be optionally substituted by 1 to 3 halogen, 1 to 3 --OR.sub.2, --CON(R.sub.2)(R.sub.2), --C(O)OR.sub.2, 1 to 3 C.sub.1 -C.sub.4 alkyl, --S(O).sub.m R.sub.2, or 1H-tetrazol-5-yl; PA1 Y is selected from: hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q (C.sub.3 -C.sub.7 cycloalkyl), --(CH.sub.2) .sub.q --K--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.q --K--(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q --K--(CH.sub.2).sub.t (C.sub.3 -C.sub.7 cycloalkyl containing O, NR2, S), and --(CH.sub.2).sub.q --K--(CH.sub.2) .sub.t (C.sub.3 -C.sub.7 cycloalkyl), where K is O, S(O).sub.m, C(O)NR.sub.2, CH.dbd.CH, C.tbd.C, N(R.sub.2)C(O), C(O)NR.sub.2, C(O)O, or OC(O), and where the alkyl, R.sub.2, (CH.sub.2).sub.q and (CH.sub.2) .sub.t groups may be optionally substituted by C.sub.1 -C.sub.4 alkyl, hydroxyl, C.sub.1 -C.sub.4 lower alkoxy, carboxyl, --CONH.sub.2 or carboxylate C.sub.1 -C.sub.4 alkyl esters, and aryl is phenyl, naphthyl, pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrazinyl, or isothiazolyl which is optionally substituted by 1 to 3 halogen, 1 to 3 --OR.sub.2, --C(O)OR.sub.2, --C(O)N(R2)(R2), nitro, cyano, benzyl, 1 to 3 C.sub.1 -C.sub.4 alkyl, --S(O).sub.m R.sub.2, or 1H-tetrazol-5-yl, with the proviso that if X is hydrogen, Y is other than hydrogen; PA1 R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, or substituted C.sub.1 -C.sub.6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C.sub.1 -C.sub.10 alkanoyloxy, 1 to 3 C.sub.1 -C.sub.6 alkoxy, phenyl, phenyloxy, 2-furyl, C.sub.1 -C.sub.6 alkoxycarbonyl, S(O).sub.m (C.sub.1 -C.sub.6 alkyl), or R.sub.4 and R.sub.5 may be taken together to form --(CH.sub.2).sub.d --L.sub.a (CH.sub.2).sub.e -- where L.sub.a is --C(R.sub.2).sub.2 --, O, S(O).sub.m or N(R.sub.2), d and e are independently 1 to 3 and R.sub.2 is as defined above; PA1 A is: ##STR3## where x and y are independently 0, 1, 2 or 3; Z is N--R.sub.6a or O, where R.sub.6a is hydrogen or C.sub.1 -C.sub.6 alkyl; PA1 R.sub.7 and R.sub.7a are independently hydrogen, C.sub.1 -C.sub.6 alkyl, trifluoromethyl, phenyl, or substituted C.sub.1 -C.sub.6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR.sub.2, S(O).sub.m R.sub.2, C(O)OR.sub.2, C.sub.3 -C.sub.7 cycloalkyl, N(R.sub.2)(R.sub.2), C(O)N(R.sub.2)(R2), or R.sub.7 and R.sub.7a may independently be joined to one or both of R.sub.4 and R.sub.5 groups to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R.sub.7 or R.sub.7a groups, wherein the bridge contains 1 to 5 carbons atoms, or R.sub.7 and R.sub.7a can be joined to one another to form C.sub.3 -C.sub.7 cycloalkyl; PA1 m is 0, 1, or 2; PA1 n is 1, 2, or 3; PA1 q is 0, 1, 2, 3, or 4; PA1 t is 0, 1, 2, or 3; PA1 R.sub.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.3 -C.sub.7 cycloalkyl, and where two C.sub.1 -C.sub.6 alkyl groups are present on one atom they may be optionally joined to form a C.sub.4 -C.sub.7 cyclic ring optionally including oxygen, sulfur or NR.sub.3a ; PA1 R.sub.3a is hydrogen, or C.sub.1 -C.sub.4 alkyl; X is selected from: hydrogen, --(CH.sub.2).sub.q N(R.sub.2)C(O)R.sub.2, --(CH.sub.2).sub.q N(R.sub.2)C(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)C(O)OR.sub.2, --(CH.sub.2).sub.q N(R.sub.2)SO.sub.2 (CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)SO.sub.2 R.sub.2, --(CH.sub.2).sub.q N(R.sub.2)C(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)C(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q C(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q C(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q C(O)OR.sub.2, --(CH.sub.2).sub.q C(O)O(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q OC(O)R.sub.2, --(CH.sub.2).sub.q OC(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q S(O)mR.sub.2, and --(CH.sub.2).sub.q S(O)m(CH.sub.2).sub.t aryl, where an R.sub.2 group may be optionally substituted by hydroxyl, carboxyl, CONH.sub.2, S(O).sub.m CH.sub.3, carboxylate C.sub.1 -C.sub.4 alkyl esters, or tetrazole, and aryl is phenyl, naphthyl, pyridyl or 1-H-tetrazolyl which may be optionally substituted by 1 to 2 halogen, 1 to 2 --OR.sub.2, --CONH.sub.2, --C(O)OR.sub.2, 1 to 3 C.sub.1 -C.sub.4 alkyl, --S(O).sub.m R.sub.2, or 1H-tetrazole-5-yl; PA1 Y is selected from: hydrogen, C.sub.1 -C.sub.8 alkyl, (CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q (C.sub.5 -C.sub.6 cycloalkyl), --(CH.sub.2).sub.q --K--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.q --K--(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q --K--(CH.sub.2).sub.t (C.sub.3 -C.sub.7 cycloalkyl containing O, NR.sub.2, or S), and --(CH.sub.2).sub.q --K--(CH.sub.2).sub.t (C.sub.5 -C.sub.6 cycloalkyl), where K is O or S(O)m and where the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH.sub.2, carboxylate C.sub.1 -C.sub.4 alkyl esters or 1H-tetrazole-5-yl and aryl is phenyl, naphthyl, pyridyl, 1-H-tetrazolyl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, or thiopheneyl which is optionally substituted by 1 to 3 halogen, 1 to 3 --OR.sub.2, --C(O)OR.sub.2, --C(O)N(R.sub.2)(R.sub.2), cyano, 1 to 2 C.sub.1 -C.sub.4 alkyl, benzyl, --S(O).sub.m R.sub.2, or 1H-tetrazol-5-yl, with the proviso that if X is hydrogen, Y is other than hydrogen; PA1 R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, or substituted C.sub.1 -C.sub.6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(O)m (C.sub.1 -C.sub.6 alkyl) or phenyl; PA1 A is: ##STR5## where x is 0, or 1; R.sub.7 and R.sub.7a are independently hydrogen C.sub.1 -C.sub.6 alkyl, trifluoromethyl, phenyl, substituted C.sub.1 -C.sub.6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR.sub.2, S(O)mR.sub.2, C(O)OR.sub.2, C.sub.5 -C.sub.7 cycloalkyl, --N(R.sub.2)(R.sub.2), --C(O)N(R.sub.2)(R.sub.2); or R.sub.7 and R.sub.7a can independently be joined to one of R.sub.4 or R.sub.5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of R.sub.7 or R.sub.7a groups to form 5 or 6 membered rings; or R.sub.7 and R.sub.7a can be joined to one another to form a C.sub.3 cycloalkyl; PA1 n is 2; PA1 m is 0, 1, or 2; PA1 q is 0, 1, 2, or 3; PA1 t is 0, 1, 2, or 3; PA1 R.sub.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.3 -C.sub.7 cycloalkyl, and where two C.sub.1 -C.sub.6 alkyl groups are present on one atom they may be optionally joined to form a C.sub.5 -C.sub.7 cyclic ring optionally including oxygen, sulfur or NR.sub.3a ; PA1 R.sub.3a is hydrogen, or C.sub.1 -C.sub.4 alkyl; PA1 X is selected from: hydrogen, --(CH.sub.2).sub.q N(R.sub.2)C(O)R.sub.2, --(CH.sub.2).sub.q N(R.sub.2)C(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)SO.sub.2 (CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)SO.sub.2 R.sub.2, --(CH.sub.2).sub.q N(R.sub.2)C(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q N(R.sub.2)C(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q C(O)N(R.sub.2)(R.sub.2), --(CH.sub.2).sub.q N(R.sub.2)C(O)OR.sub.2, --(CH.sub.2).sub.q C(O)N(R.sub.2)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q C(O)OR.sub.2, --(CH.sub.2).sub.q C(O)O(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q OC(O)R.sub.2, --(CH.sub.2).sub.q OC(O)(CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q S(O).sub.m R.sub.2, and --(CH.sub.2).sub.q S(O).sub.m (CH.sub.2).sub.t aryl, where an R.sub.2 group may be optionally substituted by hydroxyl, carboxyl, --CONH.sub.2, --S(O).sub.m CH.sub.3, carboxylate C.sub.1 - C.sub.4 alkyl esters or tetrazole and aryl is phenyl, naphthyl or pyridyl which may be further substituted by 1-2 halogen, 1 to 2 OR.sub.2, C(O)OR.sub.2, 1 to 3 C.sub.1 -C.sub.4 alkyl, S(O).sub.m R.sub.2, or 1H-tetrazole-5-yl; PA1 Y is selected from: hydrogen, C.sub.1 -C.sub.8 alkyl, (CH.sub.2).sub.t aryl, --(CH.sub.2).sub.q C.sub.5 -C.sub.7 cycloalkyl, --(CH.sub.2).sub.q --K--(C.sub.1 -C.sub.6 alkyl), --(CH.sub.2).sub.q --K--(CH.sub.2).sub.t aryl, and --(CH.sub.2).sub.q --K--(CH.sub.2).sub.t (C.sub.5 -C.sub.6 cycloalkyl), where K is S(O).sub.m and where the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH.sub.2, carboxylate C.sub.1 -C.sub.4 alkyl esters or 1H-tetrazole-5-yl and aryl is phenyl, napthyl, pyridyl, thiazolyl, thiopheneyl, pyrazolyl, oxazolyl, isoxazolyl or imidazolyl which may be optionally substituted by 1 to 2 halogen, 1 to 2 OR.sub.2, 1 to 2 -N(R.sub.2)(R.sub.2), CO(OR.sub.2), 1 to 2 C.sub.1 -C.sub.4 alkyl, S(O).sub.m R.sub.2, or 1H-tetrazol-5-yl, with the proviso that if X is hydrogen, Y is other than hydrogen; PA1 R.sub.4 and R.sub.5 are independently hydrogen, C.sub.1 -C.sub.4 alkyl, or substituted C.sub.1 -C.sub.3 alkyl where the substituents may be 1 to 2 hydroxyl; PA1 A is ##STR7## where x is 0, or 1; R.sub.7 and R.sub.7a are independently hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, substituted C.sub.1 -C.sub.6 alky wherein the substitutent is imidixolyl, phenyl, indolyl, p-hydroxyphenyl, OR.sub.2, S(O).sub.m R.sub.2, or R.sub.7 and R.sub.7a may be joined to one another to form a C.sub.3 cycloalkyl; PA1 m is 0, 1, or 2; PA1 q is 0, 1, 2, or 3; PA1 t is 0, 1, 2, or 3; PA1 R.sub.3a is hydrogen, or C.sub.1 -C.sub.4 alkyl; PA1 X is selected from the group consisting of: hydrogen, ##STR10## Y is selected from the group consisting of: hydrogen, ##STR11## or their regioisomers whereof where not specified, with the proviso that if X is hydrogen, Y is other than hydrogen; PA1 A is selected from the group consisting of: ##STR12## R.sub.4 and R.sub.5 are independently selected from the group consisting of: ##STR13## and pharmaceutically acceptable salts and individual diastereomers thereof.
A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. The instant compounds are non-peptide analogs for promoting the release of growth hormone which are stable in a variety of physiological environments and which may be administered parenterally, nasally or by the oral route.